Somatic and germline genetic variants both play a role in cancer. Somatically, amplification of genomic DNA is a common mechanism exploited by a tumor to gain a competitive growth advantage. Regions of amplification tend to span considerable distances and encompass many genes. Identification of the target loci within the amplicon will enable a refined understanding of the genetic pathways driving tumor progression. The number of target genes that have been revealed relative to the number of recurrent amplifications, however, is low. The hypothesis is that particular germline alleles within an amplicon are positively selected for during tumor evolution and therefore achieve a higher allele frequency among amplified (versus non-amplified) chromosomes. Aim 1 adapts principles from the fields of population and statistical genetics to develop the methodological tools to test the hypothesis. Aim 2 applies these tools in a systematic fashion across 1,900 tumor genomes that have been extensively characterized for amplifications. Lastly, in Aim 3, promising candidate regions will be subjected to fine mapping and validation to isolate the actual allele under selection. The heart of the dataset for this study contains over 2,000 tumors and cancer cell lines, encompassing multiple tissue types. DNA from each sample has already been profiled on Affymetrix chips for over 230,000 single nucleotide polymorphisms (SNPs) across the genome. This platform allows for integration of information across the germline (alleles) and tumor (amplifications) genomes. The novel application of statistical and population genetic techniques to this large and high-resolution dataset will facilitate the discovery of specific regions within an amplicon under positive selection. Pinpointing candidate regions suggests downstream functional assays, which can be immediately pursued. Relevance of research to public health: The identification of the specific targets of tumor amplification has already had a profound effect on the prognostic (MYCN in neuroblastoma) and therapeutic (ERBB2 in breast cancer) realms of clinical oncology. The proposed research aims to perform a genome wide survey to systematically delineate the target genes in regions of copy number gain in multiple tumor types. Discovery of the genes and pathways contributing to tumor survival and progression will allow for more refined clinical decision-making.